U.S. patent number 6,355,273 [Application Number 09/601,642] was granted by the patent office on 2002-03-12 for pharmaceutical compositions in form of polymeric microparticles obtained by extrusion and spheronization.
This patent grant is currently assigned to Eurand International, S.p.A.. Invention is credited to Massimo Bresciani, Tiziana Canal, Fabio Carli, Paolo Gambini.
United States Patent |
6,355,273 |
Carli , et al. |
March 12, 2002 |
Pharmaceutical compositions in form of polymeric microparticles
obtained by extrusion and spheronization
Abstract
Process for the preparation of pharmaceutical compositions
comprising one or more polymers and one or more drugs by the
extrusion and spheronization technique, wherein polymers belong to
the group of the cross-linked amphiphilic polymers.
Inventors: |
Carli; Fabio (Trieste,
IT), Bresciani; Massimo (Trieste, IT),
Canal; Tiziana (Trieste, IT), Gambini; Paolo
(Muggia, IT) |
Assignee: |
Eurand International, S.p.A.
(IT)
|
Family
ID: |
11378855 |
Appl.
No.: |
09/601,642 |
Filed: |
August 4, 2000 |
Foreign Application Priority Data
|
|
|
|
|
Feb 6, 1998 [IT] |
|
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MI98A0233 |
|
Current U.S.
Class: |
424/489; 424/490;
514/772.3 |
Current CPC
Class: |
A61K
9/1694 (20130101); A61K 9/1635 (20130101); A61K
9/1611 (20130101); A61K 9/1652 (20130101) |
Current International
Class: |
A61K
9/16 (20060101); A61K 009/14 (); A61K 009/16 ();
A61K 047/30 () |
Field of
Search: |
;424/489,490
;514/772.3 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Page; Thurman K
Assistant Examiner: Bennett; Rachel M.
Attorney, Agent or Firm: Thompson Hine LLP
Claims
What is claimed is:
1. Process for the preparation of pharmaceutical compositions in
form of polymeric microparticles comprising a drug and a
cross-linked amphiphilic polymer, said process comprising the steps
of:
a) preparing a homogeneous mixture of substances in powder form to
which a liquid is added to obtain a pasty consistency, wherein said
mixture comprises one or more cross-linked amphiphilic
polymers;
b) extruding the mixture of step a) through a perforated mesh in
order to obtain cylindrical filaments;
c) spheronizing the cylindrical filaments of step b) in order to
obtain microparticles in spherical form, and
d) drying the microparticles of step c).
2. Process as claimed in claim 1, wherein said cross-linked
amphiphilic polymers are selected from the group consisting of
cross-linked polyvinyl pyrrolidone, sodium carboxymethyl cellulose,
sodium glycolate starch and dextrans.
3. Process as claimed in claim 1, wherein said drug is selected
from the group consisting of drugs acting on the central nervous
system and on the peripheral nervous system, cardiovasculars,
hypotensives, diuretics, anti-inflammatories, analgesics,
antifebriles, antiasthmatics, bronchodilatators, antitussis,
mucolytics, antibiotics, chemotherapeutic agents, antivirals,
hormones, antineoplastics, immunosuppressants, immunostimulants,
peptides, polypeptides, proteins and vaccines.
4. Process as claimed in claim 1 wherein said drug is uniformly
distributed inside the microparticles.
5. Process as claimed in claim 4, wherein the drug ranges from 0.1
to 95% by weight with respect to the microparticles.
6. Process as claimed in claim 1, wherein said mixture of
substances in the form of powder comprises a cross-linked
amphiphilic polymer and a drug, obtained by high energy comilling
or by loading by solvent.
7. Process as claimed in claim 1, wherein said mixture of
substances further comprises a bioadhesive substance selected from
the group consisting of alginates, scleroglucans, chitosans,
xanthans and silicone gel.
8. Process as claimed in claim 1, wherein said mixture of
substances further comprises a high density substance selected from
the group consisting of aluminum oxide, titanium dioxide, iron
oxide, calcium carbonate and barium sulfate.
9. Process as claimed in claim 1, wherein said liquid is selected
from the group consisting of water, aqueous solutions, organic
solvents and their mixtures, saturated and unsaturated natural
oils, semisynthetic and synthetic mono-, di- and triglycerides,
liquid waxes, silicone oils, polyethylene glycols, polyglycolic
glycerides, and polyglycols.
10. Process as claimed in claim 1, wherein the amount of liquid
with respect to the mixture of substances in powder form ranges
from 1 to 80% by weight.
11. Pharmaceutical compositions in the form of microparticles
obtained by the process as claimed in claim 1, wherein said
microparticles have spherical or almost-spherical form with a
diameter ranging from 100 .mu.m to 3 mm.
12. Process as claimed in claim 1, further comprising the step
of:
e) depositing a drug on the surface of the microparticles.
13. Process as claimed in claim 3, wherein said drug is selected
from the group consisting of nifedipine and nicardipine.
14. Process as claimed in claim 4 wherein said drug and said
cross-linked polymer are present in a ratio of from about 1:3 to
about 1:5.
15. Process as claimed in claim 1 wherein said cross-linked
amphiphilic polymers do not contain ionizable functional groups.
Description
This application is a 371 of PCT/EP99/00781 filed Feb. 5, 1999.
PRIOR ART
Processes for the preparation of pharmaceutical compositions having
microparticles form, comprising the mixing of an active principle
with suitable excipients, the extrusion through a mesh in order to
form cylindrical filaments and the subsequent spheronization are
known.
The fundamental problem of the technique of these processes is that
the mixture which is extruded must be sufficiently plastic to allow
the stability of the cylindrical filaments form and sufficiently
malleable to transform said cylindrical filaments in spherical
particles by spheronization. It is possible to use several machines
to obtain spherical microparticles: for example, high efficiency
granulators, frontal or axial extruders, fluid bed rotogranulators,
radial extruders, coaxial double screw extruders, etc. However,
notwithstanding the fact that the used plants are of different
kind, the known extrusion/spheronization techniques are based on
the use of mixtures containing microcrystalline cellulose
(AVICELL.TM.) in percentages ranging from 10 to 20%, whose
properties allow the conferring and the maintainment of the
necessary plasticity and malleability during the whole process (R.
E. Connor and J. B. Schwartz, Drug Dev. Ind. Pharm. 2, 1837, 1985).
In order to overcome this problem different techniques which,
however, show notable drawbacks have been proposed.
The U.S. Pat. No. 5,049,394 proposes to decrease the
microcrystalline cellulose percentages using mixtures of solvents
(for example water/ethanol) in spite of water only in order to
moisten the dusts.
The U.S. Pat. No. 5,350,584 suggests the use of ionic resins in
order to give the desired plasticity to the material to extrude and
spheronize. Both the solutions present some applicative limitations
because it may be necessary, for some kinds of formulations or in
case of incompatibility, to avoid the use of solvents or ionized
materials.
A solution proposed to overcome the problems related to the
plasticity of the mixture to extrude considers the melting at a
suitable temperature of the mixture itself (WO 96/25149 and WO
96/25151). The limitation of this solution lies in the necessity to
use thermostable materials and active principles.
Other solutions consider the use of high amounts (to 50%) of
plasticizing substances (JP 2527107) allowing to keep plastic the
mass to extrude. Such technique strongly limits the amount of
active principle which may be introduced in the mass to extrude and
moreover it can cause compatibility problems among the
materials.
SUMMARY
Now we have unexpectedly found that the problems of the prior art
are solved using, for the preparation of microparticles by
extrusion and spheronization, compositions comprising cross-linked
amphiphilic polymers.
Therefore the present invention relates to a process for the
preparation of pharmaceutical compositions in form of polymeric
microparticles comprising:
a) the preparation of a homogeneous mixture of substances in powder
form to which a liquid to a pasty consistence is added;
b) the extrusion of the mixture of the step a) through a perforated
mesh in order to obtain cylindrical filaments;
c) the spheronization of the cylindrical filaments of the step b)
in order to obtain microparticles in spherical form, and
d) the drying of the microparticles of the step c),
e) optionally drug is deposited on the surface of the
microparticles, characterized in that said mixture of substances in
powder form consists of one or more cross-linked amphiphilic
polymers and optionally one or more drugs, excipients, a
bioadhesive substance and/or a substance having high density.
The process according to the present invention shows several
advantages with respect to the prior art because it does not ask
for the presence of plasticizing, linking substances, solvents or
linear polymers and it allows the incorporation of high percentages
of drugs having different characteristics of solubility and
wettability.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 represents the microparticles obtained by the example 6
procedure, determined by scanning electron microscopy.
DETAILED DESCRIPTION OF THE INVENTION
The process described in this invention relates to the production
of pharmaceutical compositions in form of microparticles or
spherical multiparticulates based on cross-linked amphiphilic
polymers by the following steps:
a) the mixing of one or more cross-linked amphiphilic polymers with
one or more active principles, when needed, and optionally other
pharmaceutical excipients in order to obtain a uniform mixture in
form of dry powder to which a suitable amount of liquid is added to
obtain a pasty consistency;
b) the extrusion of the mixture obtained from the step a) through a
perforated mesh in order to obtain cylindrical filaments having
desired length and diameter;
c) the spheronization of the filaments in order to obtain a product
in the form of spherical multiparticulates;
d) the drying of the product;
e) the optional depositing of a drug on the surface of the
microparticles.
With the expression "spherical multiparticulate" we mean spherical
or almost-spherical microparticles whose diameter size may range
from about 100 .mu.m to about 3 mm.
With the expression "cross-linked amphiphilic polymer" we mean a
polymer showing characteristics of swellability in the whole pH
range of aqueous solutions and also in solvents or solvent mixtures
having different polarity characteristics. The polymers may be
cross-linked either physically, through the interpenetration of the
macromolecular meshes, or chemically, thus showing points of link
among the macromolecular chains.
Significant but not limitative examples of such polymers comprise
cross-linked polyvinyl pyrrolidone, sodium carboxymethylcellulose,
sodium glycolate starch and dextrans. Optional excipients consist
of dispersing, emulsifying, wetting or colouring agents.
With the expression "active principle" we mean any physiologically
or pharmacologically acceptable substance, organic or inorganic, of
natural or synthetic origin, producing systemic or local effects in
living beings. The active principles which may be vehiculated by
the microparticles of this invention comprise drugs acting on the
central nervous system and on the peripheral nervous system,
cardiovasculars, hypotensives, diuretics, anti-inflammatories,
analgesics, antifebriles, antiasthmatics, bronchodilatators,
antitussis, mucolytics, antibiotics, chemotherapeutic agents,
antivirals, hormones, antineoplastics, immunosuppressants,
immunostimulants, peptides, polypeptides, proteins, vaccines and so
on.
Among the drugs which may be formulated according to the invention
we may mention, for example:
ergot alkaloids and derivatives: dihydroergotamine,
dihydroergotoxine, bromocriptine.
Analgesics and non steroidal anti-inflammatories, and their salts:
diclofenac sodium, diclofenac hydroxyethyl pyrrolidine, diclofenac
diethylamine, ibuprofen, flurbiprofen, ketoprofen, indomethacin,
mefenamic acid, naproxen, nimesulide, piroxicam.
Antiarrhythmics: amiodarone, diisopyramide, propranolol,
verapamil.
Antibacterials: amoxicillin, flucloxacillin, gentamicin,
rifampicin, erythromycin, cephalosporins.
Antifungals and antipsoriatics: amphotericin, butoconazole nitrate,
ketoconazole, econazole, etretinate, fluconazole, flucytosine,
griseofulvin, itraconazole, miconazole, nystatin, sulconazole,
tioconazole.
Antivirals: acyclovir, ganciclovir, AZT, protease inhibitors.
Antihypertensives: amlodipine, clonidine, diltiazem, felodipine,
guanabenz acetate, isradipine, minoxidil, nicardipine
hydrochloride, nimodipine, nifedipine, prazosin hydrochloride,
papaverine.
Antidepressants: carbamazepine.
Antihistaminics: diphenhydramine, chlorpheniramine, pyrilamine,
chlorcyclizine, promethazine, acrivastine, cinnarizine, loratadine,
terfenadine.
Antineoplastics and immunosuppressants: cyclosporin, dacarbazine,
etretinate, etoposide, lomustine, melphalan, mitomycin,
mitoxantrone, paclitaxel, procarbazine, tamoxifen, taxol and
derivatives, taxotere.
Anxiolytics, sedatives, hypnotics: alprazolam, bromazepam,
diazepam, lorazepam, oxazepam, temazepam, sulpiride, triazolam.
.beta.-Blockers: alprenolol, oxprenolol, pindolol, propranolol.
.beta.-Agonists: salbutamol, salmeterol.
Cardiac and cardiovascolar inotropics: amrinone, digitoxin,
digoxin, lanatoside C, medigoxin, ubidecarenone.
Corticosteroids: beclomethasone, betamethasone, budesonide,
cortisone acetate, desoximethasone, dexamethasone, fludrocortisone
acetate, flunisolide, hydrocortisone, methyiprednisone,
triamcinolone.
Gastrointestinals and anti H2-histaminics: cimetidine, cisapride,
domperidone, famotidine, loperamide, mesalazine, omeprazole,
ondansetron hydrochloride, ranitidine.
hypolipidemics: bezafibrate, clofibrate, gemfibrozil, probucol,
lovastatin.
Anti-anginals: amyl nitrate, glyceryl trinitrate, isosorbide
dinitrate and mononitrate, pentaerythritol tetranitrate.
Central Action Drugs: for example nicotine.
Vitaminic and Nutritional Agents: betacarotene, vitamin A, Vitamin
B2, Vitamin D and derivatives, vitamin E and derivatives, vitamin
K.
Opioid Analgesics: codeine, dextropropoxyphene, diihydrocodeine,
morphine, pentazocine, methadone.
Sexual Hormones: danazol, ethinyl estradiol, medroxyprogesterone
acetate, methyltestosterone, norethisterone, norgestrel, estradiol,
estriol, progesterone, stilbestrolo, diethylstilbestrol.
Peptidic, proteic or polysaccharidic molecules having different
activity:
leuprolide and LH-RH analogues, calcitonin, glutathione,
somatotropin (GT), somatostatin, desmopressin (DDAVP), interferon,
molgramostin, epidermic growth factor (EGF), nervous growth factor
(NGF), insulin, glucagon, toxins or toxoides (for example tetanus
toxin), antigenic factors of proteic or polysaccharidic kind,
heparin having low molecular weight, heparinoids.
The active principles may be uniformly distributed inside the
microparticles or they may be deposited on the surface of the
microparticles by techniques normally used in the pharmaceutical
processes (for example, spray drying, coating in basins, and so
on).
In the case that an active principle is distributed inside the
microparticles, it ranges from about 0.1% to about 95% by weight of
the microparticles.
A particular embodiment of this invention relates to the
extrusion/spheronization of the active principles included and/or
charged on cross-linked amphiphilic polymers according to the
techniques disclosed in the Patents EP 0 371 431, U.S. Pat. No.
5.449.521, EP 0 364 944, U.S. Pat. No. 5,569,469, PCT
IB96/00492.
In these cases composite materials consisting of active
principle/cross-linked amphiphilic polymer, obtained by high energy
comilling or solvent loading techniques, are extruded. An advantage
of this particular application consists in the coupling between
improved solubility and bioavailability of the active principle
obtained by the techniques described in the cited Patents and the
improved technological characteristics of the microparticles, which
allows its immediate application without further formulative
passages.
With the term "excipients" we mean substances commonly used in the
pharmaceutical technique as linking, dispersing, emulsifying,
wefting or colouring agents. Not exhaustive examples of such
excipients may be found in "Handbook of Pharmaceutical Excipients",
2nd Edition, American Pharmaceutical Association, 1994.
A particular embodiment of this invention relates to the
preparation of spherical multiparticulates to which selected
excipients give the bioadhesiveness and/or high density
characteristics according to what is disclosed in the Patent EP 0
526 862.
Among the substances suitable to give bioadhesiveness we may
mention for example: sodium alginate, scleroglucan, chitosan,
xanthan, silicone gel, and so on.
Among the substances suitable to give high density we may mention
not exhaustively: aluminium oxide, titanium dioxide, iron oxide,
calcium carbonate, barium sulfate, and so on.
With the expression "uniform mixture" we mean that the components
of the mixture are uniformly dispersed in the formulation by a
mixing process which assures the uniform distribution of each
component.
A reasonable mixing time may range from 1 to 60 minutes using one
of the mixing equipments normally used for the dry mixing of the
powders (for example: "V", fixed body, rotating body, sigma mixers
and so on).
With the term "liquid" we mean any liquid substance or mix
(solution or emulsion) of liquids of normal pharmaceutical use able
to moisten the powder mix, as for example water, aqueous solutions
having different pH, organic solvents of normal pharmaceutical use
(for example, alcohols, chlorinated solvents, and so on), oils.
Among the oils which may be used we cite for example: natural oils,
either saturated or unsaturated (olive, peanut, soybean, corn,
coconut, palm, sesame and similar oils); semisynthetic and
synthetic mono-, di- and triglycerides containing saturated and/or
unsaturated fatty acids and their polyhydroxyethylated derivatives
(caprico-caprilic triglycerides [Mygliol.TM., Captex.TM.,
Labrafac.TM., Lipo], saturated or unsaturated polyhydroxylated
triglycerides of various kind [Labrafil.TM., Labrafac.TM. Hydro,
Gelucire.TM.]); liquid waxes (isopropyl myristate,
isopropyl-caprinate, -caprylate, -laurate, -palmitate, -stearate);
fatty acids esters (ethyl oleate, oleyl oleate); silicone oils;
polyethylene glycols (PEG 200, PEG 400, PEG 600, PEG 1000, and so
on); polyglycolic glycerides (for example Labrasol.TM.);
polyglycols (propylene glycol, tetraglycol, ethoxydiglycol
(Transcutol.TM.).
For example all the non ionic surfactants may be mentioned among
the surfactants: sorbitan-esters of fatty acids (for example
Span.RTM., Arlacel.RTM., Brij.RTM.), polyoxyethylenesorbitan esters
of fatty acids (for example Tween.RTM., Capmul.RTM.,
Liposorb.RTM.), polypropylene oxide-polyethylene oxide (Poloxamer)
copolymers, polyethylene glycol esters (PEG)-glycerol
(Labrasol.RTM., Labrafil.RTM.), PEG esters and long chain aliphatic
acids or alcohols (for example Cremophor.RTM.), polyglycerid esters
(Plurol.RTM.), saccharide and fatty acid esters (sucro-esters).
Moreover, anionic surfactants (for example sodium lauryl sulfate,
sodium stearate, sodium oleate) or cationic surfactants (for
example tricetol), may be used as well as lecithins, phospholipids
and their semi-synthetic or synthetic derivatives.
Moreover active principles and/or excipients may be dissolved,
dispersed and/or emulsified in such liquids.
In a particular embodiment of the invention, the moistening liquid
consists of an oil/surfactant system wherein the active principle
optionally emulsified with an aqueous phase is dissolved or
dispersed. The amount of liquid with respect to the solid used in
the preparation of the mixture of the step a) ranges from 1 to 80%
by weight.
The moistened mass is extruded through a perforated mesh in order
to produce cylindrical filaments. The port of the meshes determines
the diameter of the filaments. A port ranging from about 0.2 mm to
about 3 mm may be used in this process. Preferably, in this
process, the port ranges from about 0.4 mm to 2 mm. The extrusion
may be carried out using screw, double screw, "sieve and basket"
kind, "roll extruder", "ram extruder" extruders or any other
pharmaceutically acceptable means to produce cylindrical filaments.
In some particular embodiments of this invention a double screw
coaxial extruder may be used.
The filaments obtained by extrusion may be directly stocked or
spheronized.
The spheronization device consists of a hollow cylinder with a
horizontal rotating plate. The filaments are broken in short
segments which are transformed in spherical or quasi-spherical
particles on the upper surface of the rotating plate at a velocity
ranging from about 200 rpm to about 2,000 rpm.
The particles may be dried in any pharmaceutically acceptable way,
such as for example the air drying or in a static condition or
their combination. The particles are used as they are or they are
coated to obtain granules to use in tablets, capsules, packets and
other pharmaceutical formulations.
Unexpectedly, operating according to the present invention, the
extruded mixture has physical characteristics which allow to
maintain the cylindrical form of the extrusion filaments and to
transform said filaments in spherical microparticles also without
the addition of plasticizers, binders, solvents or linear polymers
neither to the mixture nor to the moistening liquid, as described
in the above techniques. This moreover allows to limit possible
compatibility problems between the possibly incorporated active
principle and the excipients. Moreover, the amphiphilic
characteristics of the cross-linked polymers and their capacity to
swell in the presence of physiological liquids, allow an improved
dissolution velocity of the active principle. Moreover the obtained
microparticles show good physical characteristics (for example,
hardness, density, intraparticle porosity, and so on) which make
them suitable for a direct use (for example, direct compression,
encapsulation or distribution in packets).
The following Examples are reported for illustrative but not
limitative aim of the invention.
EXAMPLE 1
Preparation of Microparticles Consisting of Explotab
For the preparation of this Example a double screw extruder is used
having the following dimensional characteristics: screw diameter=30
mm, head length 10 diameters and a head equipped with a threader
having hole diameter equal to 1 mm.
Said extruder is fed with Explotab.TM. (sodium glycolate starch,
Mendell) in the form of powder having granulometry lower than 140
mesh; demineralized water is fed together with Explotab.TM..
The extrusion is carried out according to the following operative
parameters:
Explotab flow rate: 6 kg/h
Demineralized water flow rate: 2.1 kg/h
Torsional stress: 17%
Extruder head temperature: 13.degree. C.
Screw rotation velocity: 60 rpm.
Extrusion filaments having an excellent form stability are
obtained.
Then said filaments are treated in a spheronizator having a
velocity equal to 800 rpm for 3 minutes, obtaining a product in the
form of microparticles which are dried in a stove at 70.degree. C.
for 12 hours.
The obtained microparticles show the following characteristics:
apparent density: 0.710 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 87%.
EXAMPLES 2 AND 3
The Example 1 is repeated with the difference that Kollidon Cl.TM.
(cross-linked polyvinyl pyrrolidone, Basf) and Ac Di Sol.TM.
(cross-linked sodium carboxymethyl cellulose, FMC) are respectively
used and that one operates with a screw rotation velocity
respectively equal to 140 rpm and 100 rpm, with torsional stress
respectively equal to 30% and 15% and with a temperature of the
extruder head respectively equal to 35.degree. C. and 20.degree.
C.
The obtained microparticles show the following characteristics:
microparticles consisting of Kollidon Cl:
apparent density: 0.496 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 96%
microparticles consisting of Ac Di Sol:
apparent density: 0.538 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 92%
EXAMPLE 4
Preparation of Microparticles Consisting of a Mixture of Explotab
and Kollidon CL
A mixture consisting of 50% by weight of Explotab.TM. and 50% by
weight of Kollidon Cl.TM., using a planetary mixer with a mixing
time equal to 20 minutes is prepared.
The extrusion, the spheronization and the drying are carried out
according to the Example 1,working with a torsional stress equal to
18%, with an extruder head temperature equal to 24.degree. C. and
with screw rotation velocity equal to 140 rpm. The obtained
microparticles have the following characteristics:
apparent density: 0.598 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 91.6%.
EXAMPLES 5 AND 6
The Example 4 is repeated with the difference that the mixtures
consist respectively of Explotab.TM. and Ac Di Sol.TM. and of
Kollidon Cl.TM. and Ac Di SO.TM. (these products have been defined
in the above Examples).
The extrusion, the spheronization and the drying are carried out
according to the Example 1,working with a torsional stress
respectively equal to 15% and 25%, with an extruder head
temperature respectively equal to 22.degree. C. and 35.degree. C.
and with rotation velocity of the screws respectively equal to 80
rpm and 140 rpm. Moreover, the mixture Explotab/Ac Di Sol has been
extruded using a 0.4 mm threader and characterized using the
scanning electron microscopy (SEM) (FIG. 1).
The obtained microparticles have the following characteristics:
microparticles consisting of Explotab and Ac Di Sol:
apparent density: 0.596 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 87% (see
photo).
Microparticles consisting of Kollidon Cl and Ac Di Sol:
apparent density: 0.521 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 95.6%.
EXAMPLE 7
The Example 1 is repeated feeding the Kollidon ClM.TM. as polymer
and a 50/50 w/o emulsion as wetting liquid, wherein the oily part
consists of 95% Labrafac Hydro 9.TM. (polyhydroxylated
triglyceride) and of 5% Tween 80.TM. (polysorbate 80, Sigma).
The mixture is extruded through a threader having a diameter of the
holes equal to 0.75 mm operating according to the following
parameters:
Kollidon ClMTM flow rate: 3.9 kg/h
Wetting liquid flow rate: 38.8 kg/h
Torsional stress: 22%
Extruder head temperature: 35.degree. C.
Screw rotation velocity: 140 rpm.
The spheronization and the drying are carried out according to the
Example 1.
A product is obtained consisting of microparticles having the
following characteristics:
apparent density: 0.488 g/cm.sup.3
fraction ranging from 0.5 mm to 0.9 mm: 88.2%.
EXAMPLE 8
Preparation of Microparticles Containing Nifedipine as an Active
Substance
A mixture of nifedipine and Kollidon CLM.TM. (defined in the above
Examples) in a ratio equal to 1/3 by weight is comilled obtaining
the mixture in the form of powder having the 100% of granulometry
lower than 50 .mu.m.
The mixture is moistened using as liquid demineralized water
containing Kollidon 25.TM. (polyvinyl pyrrolidone, Basf) in a
solution 3% w/w. The extrusion is carried out forcing the moistened
mass through a threader having diameter of the holes equal to 1
mm.
The operative parameters are the following:
Powder flow rate: 4.5 kg/h
Liquid flow rate: 4.1 kg/h
Torsional stress: 27%
Head temperature: 46.degree. C.
Screw rotation velocity: 140 rpm.
The extrusion filaments are then processed in a spheronizator
adjusted at a velocity equal to 1,000 rpm for 2 minutes. The
obtained microparticles are then dried in a fluid bed for 2 hours
to a maximum temperature equal to 59.degree. C. At the end of the
drying the product is discharged and it is mechanically screened
separating the fraction ranging from 0.7 mm to 1.2 mm, which forms
the 91% by weight of the product.
The microparticles have an apparent density equal to 0.556
g/cm.sup.3.
The dissolution velocity of the so obtained pellets, determined
using the USP Paddle method (Apparatus 2), in sink conditions in pH
7.5 buffer, is reported.
Time (min.) Released % 2 34.9 5 56.0 10 77.7 20 89.3 30 98.6
EXAMPLE 9
The Example 8 is repeated with the difference that the mixture
consists of nifedipine and Explotab.TM. (defined in the above
Examples) in a ratio 1/5 by weight.
The obtained microparticles have the following characteristics:
apparent density: 0.544 g/cm.sup.3
diameter fraction ranging from 0.8 mm to 1.4 mm: 87.5%.
EXAMPLE 10
Preparation of Microparticles Containing Nifedipine as an Active
Substance
An activated system obtained by loading nifedipine by solvent, and
Kollidon CLM.TM. (defined in the above Examples) are mixed in a
ratio 1/5 by weight in the form of powder having 100% granulometry
lower than 50 .mu.m.
The mixture is moistened using as wetting liquid demineralized
water containing Kollidon 25.TM. (polyvinyl pyrrolidone) in a 2%
solution. The extrusion is carried out forcing the humid mass
through a threader having diameter of the holes equal to 1 mm. The
operative parameters are the following:
Powder flow rate: 3.3 kg/h
Liquid flow rate: 2.2 kg/h
Torsional stress: 39%
Head temperature: 55.degree. C.
Screw rotation velocity: 140 rpm.
The extrusion filaments are then processed in a spheronizator
adjusted at a velocity equal to 1,000 rpm for 2 minutes. The
obtained microparticles are then dried in a fluid bed for 2 hours
to a maximum temperature equal to 59.degree. C. At the end of the
drying the product is mechanically screened separating the fraction
ranging from 0.7 mm to 1.2 mm, which forms the 94.2% by weight of
the product. The microparticles have an apparent density equal to
0.511 g/cm.sup.3. The dissolution velocity of the so obtained
pellets, determined using the USP Paddle method (Apparatus 2), in
sink conditions in a pH 7.5 buffer, is reported.
Time (min.) Released % 3 52.2 5 69.5 15 81.6 30 88.8 60 90.6
EXAMPLE 11
Preparation of Microparticles Containing Nicardipine as an Active
Substance Kollidon CLM as a Carrier and Barium Sulfate as a High
Density Substance.
The Example 8 is repeated with the mixture in the form of powder
consisting of barium sulfate, nicardipine and Kollidon CLM.TM.
(ratio 1/3).
The extrusion is carried out according to the following operative
parameters:
Powder flow rate: 4.1 kg/h
Liquid flow rate: 3.05 kg/h
Torsional stress: 35%
Head temperature: 38.degree. C.
Screw rotation velocity: 140 rpm.
The extrusion filaments are then treated in a spheronizator
adjusted at a velocity equal to 1,000 rpm for 4 minutes. The
obtained microparticles are then dried in a fluid bed for 2 hours
to a temperature equal to 75.degree. C. At the end of the drying
the product is mechanically screened separating the fraction
ranging from 0.5 mm to 1.2 mm, which forms the 92.15% by weight of
the product.
The microparticles have the following quantitative composition:
Barium sulfate 10.00% by weight Nicardipine 22.50% by weight
Kollidon CLM 67.50% by weight
The microparticles have density characteristics at the pouring
equal to 0.756 g/cm.sup.3.
* * * * *